Solid particles, particularly small particles of controllable size and composition, find utility in a variety of industries. Among other advantages, particles of controlled size and composition provide for greater consistency and predictability in handling and use. For example, small particles of substantially identical size possess favorable flow characteristics and exhibit little variation in interparticle behavior. When such particles are used in conjunction with a chemical process, uniformity in particle size allows the particles to behave and function consistently, an attribute that is especially advantageous for the pharmaceutical industry, where the particle size of a therapeutic agent can affect the dissolution rate, bioavailability, and overall stability of the agent.
Pulmonary drug delivery relies on inhalation of a drug dispersion or aerosol by a patient so that the active agent within the dispersion can reach the alveoli of the lungs for absorption into blood circulation. As discussed in U.S. Pat. No. 5,740,794 to Smith et al., pulmonary delivery is well suited for the delivery of proteins and polypeptides, which are sometimes difficult to deliver by other routes of administration. In particular, protein and polypeptide drugs may be readily formulated as dry powders, since many otherwise labile proteins and polypeptides can be stably stored as lyophilized or spray-dried powders by themselves or in combination with suitable particulate carriers.
Since drug release rate is directly related to the surface area and size of a particle containing the drug, precise control of the particle size is particularly important in regulating the rate of drug release. In addition, the dosage of many protein and polypeptide drugs must be precisely controlled in order to deliver the intended amount of drug for efficacy without overdosing. As proteins and polypeptides are typically more costly than conventional drugs, the ability to efficiently deliver a dry powder to the target region of the lungs with a minimal loss of drug is economically desirable.
Pulmonary delivery of a powdered therapeutic agent requires specifically sized particles, generally having a diameter on the order of about 1 μm to about 7 μm. Particles that are too large tend to be deposited within the throat, while particles that are too small may be exhaled. In either case, the therapeutic agent is misdirected and does not reach the target region of the lungs. Thus, a critically important consideration in the development of particulate pharmaceutical products is the ability to produce uniform particles of an appropriate size that contain a therapeutic agent.
It should be noted that optimal particle size for rapid drug absorption through alveolar membranes to bring about a desired pharmacokinetic effect is on the order of 100 nm or smaller. Particles having a size of less than about 1 μm tend to drift, often do not reach the alveolar membrane, and may be transported out of the body when a patient exhales. It would be desirable, therefore, to be able to inexpensively create pharmaceutical particles on the size scale of about 10 nm to 100 nm, which would be attached to larger carrier particles of about 5 μm. Such amalgamated particles would be particularly suited for rapid and efficient pulmonary delivery.
Various approaches for attaining small and uniform particles have been employed. Conventional comminution techniques, e.g., crushing, grinding and milling, rely on mechanical forces to break apart relatively large particles into smaller particles. When grinding and/or milling media are used, there is a potential for contamination. Other drawbacks to mechanical comminution techniques include, for example, the potential for damage to proteins and other therapeutic biomolecules, as well as the wide variation in particle size produced by such techniques. Large variations in particle size also limit the ability to produce sustained-release formulations and result in the waste of therapeutic agents. Although it is possible to sort comminuted particles to provide a more narrow particle size distribution, large quantities of particles not having the desired size are eliminated. In addition, the process of sorting represents another potential source of contamination.
Alternatively, pharmaceutical particles of a controlled size may be produced using conventional precipitation/crystallization methods. In such methods, the therapeutic agent is initially dissolved in a suitable solvent. In one approach, the temperature of the solution is changed so that the solubility of the solute is decreased. In another approach, a second solvent, an “antisolvent,” is added so that the solubility of the solute is decreased. In both approaches, the solute precipitates or crystallizes out of the solution due to reduced solubility in the altered solution. These methods, however, often require toxic solvents, result in wet particles (that require further processing, e.g., drying), and may also produce particles with considerable size variation.
In some instances, supercritical fluid technology, such as the rapid expansion of supercritical solutions (known as the “RESS” method), is employed. Although use of supercritical fluid technology enables the production of relatively small particles of uniform size, such methods are not without drawbacks. One problem associated with supercritical fluid handling methods is their reliance on nozzles and tubes for delivering the solutions. Nozzles are known to wear down over time, thus altering the geometry of the equipment and affecting the size of the droplets formed. Also, nozzles may become blocked during use, when, for example, particles agglomerate upon rapid expansion within the nozzle bore. In addition, nozzles and associated components require cleaning and may contaminate solutions when not properly maintained. Furthermore, the resulting droplet sizes are relatively varied for both supercritical and conventional solutions that are produced by methods relying on nozzles, leading to a large variance in surface tension between the differently sized droplets. At the droplet sizes required for supercritical methods, the differences in surface tension between droplets can cause wide variations in crystallization kinetics and growth, leading to the formation of differently sized particles. U.S. Pat. No. 5,874,029 to Subramaniam et al. describes methods for producing small-sized droplets using nozzles; however, these methods are still unable to effectively and consistently produce droplets of uniform size.
Nozzleless approaches to formation of liquid droplets containing pharmaceutical agents have been described. U.S. Patent Application Publication No. 20020077369 to Noolandi et al., for example, describes focused acoustics to generated liquid droplets from a single bulk fluid near an airway for direct inhalation. The focused acoustic energy may be used in two ways: either to generate liquid droplets whose diameter is on the order of the acoustic wavelength as described in U.S. Pat. No. 4,308,547 to Lovelady et al. or alternatively by capillary wave generation using shorter bursts as described in U.S. Patent Application Publication No. 20020073989 to Hadimioglu. Formation of solid particles by these nozzleless approaches is not described.
Thus, there is a need in the art for improved particle formation techniques, wherein particle formation is highly reproducible, controllable, and predictable. An ideal method would minimize or eliminate contact of the particle-forming fluid(s) with processing equipment surfaces or contaminants adsorbed thereon. The present invention addresses the aforementioned need in the art by using focused acoustic energy to eject particle-forming droplets from a solution containing a compound of interest as a solute, and by subjecting the droplets to conditions that allow the compound to precipitate out of solution.